Paraguayan Victor Aquino struck twice early in the second half to hand the Rosario side's new coach Alfredo Berti the win at La Bombonera on Tuesday.
The match was postponed from the opening weekend at the beginning of the month to give Newell's a longer break after they reached the South American Libertadores Cup semi-finals deep into the off-season.
Striker Nicolas Blandi gave Boca a fourth-minute lead and former Atletico Madrid defender Daniel Diaz put them back in front after half an hour following Milton Casco's equaliser.
"Our distractions cost us the defeat... We're going to work on our concentration and scaling (in defence)," Boca coach Carlos Bianchi, whose team started the championship as title favourites, told reporters.
Boca, who opened the season with a controversial 2-1 win at Belgrano in which they benefited from two dubious offside calls, have three points from two matches.
San Lorenzo are the only team with a maximum six points at the top of the standings in the 'Inicial' championship, the first of two in the 2013-14 season.